Measles virus (MV) is a pathogenic virus of the family Paramyxoviridae, genus Morbillivirus, which causes immunosuppression or respiratory symptoms to a human who has been infected as a natural host. Since a mechanism whereby tumor cells are infected with the measles virus so that the virus induces regression of the tumor has been revealed (Non Patent Literature 1), the measles virus has attracted attention as a tool used in the virotherapy for cancer. To date, clinical studies regarding the virotherapy of using the measles virus based on vaccine strains have been conducted for ovary cancer and myeloma (Non Patent Literature 2).
Upon infection of host cells with the measles virus, this virus uses three molecules as receptors. These molecules are CD46 (Non Patent Literature 3 and Non Patent Literature 4), SLAM (signaling lymphocyte activation molecule) (Non Patent Literature 5), and PVRL4 (Poliovirus receptor related 4, which is also referred to as “Nectin-4”) (Non Patent Literature 6 and Non Patent Literature 7). Vaccine strains of the measles virus can use all of these three molecules as receptors. However, wild-type measles virus strains can use PVRL4 and SLAM, but they cannot use CD46. CD46 is ubiquitously present in human nucleated cells, and in particular, the expression of CD46 is increased in tumor cells (Non Patent Literature 8 and Non Patent Literature 9). Thus, some virotherapy development studies using measles virus vaccine strains have targeted a principal receptor CD46. However, since CD46 is also expressed in normal cells, it has been problematic in terms of side effects and an influence on the infection rate to target tumor cells. Moreover, in the case of subjects who received vaccination, early stage elimination caused by immunity is also concerned.
The expression of PVRL4 is selectively increased in tumor cells including breast cancer cells, ovary cancer cells, and lung cancer cells (Non Patent Literature 10 to Non Patent Literature 13). In general, PVRL4 is expressed in human placenta, and the expression thereof is hardly observed in other tissues (Non Patent Literature 14).
The present inventors have conceived of using a wild-type measles virus strain to selectively target PVRL4. The receptor for the wild-type measles virus exhibiting pathogenicity is SLAM. SLAM is selectively expressed in immune cells, and enables serious immunosuppression by the measles virus and diffusion of the virus to the entire body (Non Patent Literature 15). Hence, the inventors have produced a recombinant measles virus that does not recognize SLAM (rMV-SLAMblind), based on the wild-type measles virus strain HL (Non Patent Literature 16 and Patent Literature 1). When breast cancer cells are infected with rMV-SLAMblind in vitro or in vivo, the cancer cells can be killed. The antitumor activity of rMV-SLAMblind is higher than that of conventional measles virus vaccine strains. In addition, rMV-SLAMblind has been completely attenuated, and thus, it has been confirmed that rMV-SLAMblind does not cause the typical clinical symptoms of measles, when it is subcutaneously inoculated into a monkey, and thus that this recombinant virus is highly safe (Non Patent Literature 16 and Patent Literature 1).
As stated above, a recombinant measles virus that does not recognize SLAM, rMV-SLAMblind, is expected to be an extremely effective tool for cancer therapy. In particular, rMV-SLAMblind is greatly expected for the treatment of, not only primary cancer, but also metastatic cancer, and it is also greatly expected to have cytotoxic effects on cancer stein cells.